Compounds known to have antifolate activity are well recognized as chemotherapeutic agents for the treatment of cancer. One such agent, methotrexate, is now one of the most widely used anticancer drugs; and many other compounds in the folic acid family have been synthesized, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level. In particular, they inhibit such enzymes as dihydrofolate reductase, folate polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthase.
More recently, a series of 4-hydroxypyrrolo-[2,3-d]pyrimidine-L-glutamic acid derivatives have been disclosed and shown to be particularly useful antifolate drugs. See, e.g., Akimoto, et al., European Patent Publication 0 434 426.
5-Substituted pyrrolo[2,3-d]pyrimidine compounds of the formula I ##STR1## wherein R is NHC*H(COOR.sup.1)CH.sub.2 CH.sub.2 COOR.sup.1 or OR.sup.1 ;
each R.sup.1 is H or the same or different carboxy protecting group; PA1 the configuration about the carbon atom designated * is L; PA1 each R.sup.1 is H or the same or different carboxy protecting group; PA1 the configuration about the carbon atom designated * is L; PA1 n is 0 or 1; and PA1 A is an aryl group which may be substituted; PA1 or a salt thereof, which comprises PA1 a) reacting a halogenating agent with a compound of formula III ##STR5## wherein R, R.sup.1, A, n and * are as defined above; and PA1 b) reacting the reaction product from step a) with 2,4-diamino-6-hydroxypyrimidine; and PA1 c) optionally salifying the reaction product from step b). PA1 R is OR.sup.1; PA1 R.sup.1 is H or a carboxy protecting group; PA1 n is 0or 1; PA1 R.sup.3 is OR.sup.4 ; and PA1 R.sup.4 is a hydroxy protecting group, as generally described by DeGraw, supra, with a compound of formula VIII ##STR9## wherein each R.sup.1' is the same or different carboxy protecting group and the configuration about the carbon atom designated * is L, using conventional condensation techniques. One preferred condensation method, when R of a formula II compound is H, is taught by Taylor, et al., in U.S. Pat. No. 4,684,653. Otherwise, a formula II compound should first be deprotected prior to condensation. PA1 each R.sup.1 is H or the same or different carboxy protecting group; PA1 the configuration about the carbon atom designated * is L; PA1 n is 0 or 1; and PA1 A is an aryl group which may be substituted; PA1 or a salt thereof, which comprises PA1 a) reacting a halogenating agent with a compound of formula III ##STR12## wherein R, R.sup.1, A, n and * are as defined above; and PA1 b) reacting the reaction product from step a) with 2,4-diamino-6-hydroxypyrimidine; and PA1 c) optionally salifying the reaction product from step b).
n is 0 or 1; and
A is an aryl group which may be substituted, are useful in preparing various 5-substituted pyrrolo[2,3-d]pyrimidine-based therapeutic agents or, when R is NHC*H(COOR.sup.1)CH.sub.2 CH.sub.2 COOR.sup.1 and each R.sup.1 is H, or a salt thereof, are useful as therapeutic agents.
The art recognizes multiple methods for the preparation of pyrrolopyrimidine derivatives. See, e.g., U.S. Pat. No. 4,997,838; Miwa, et al., J Med. Chem., 34: 555-560 (1991); C.W. Noell, et al., J. Heterocyclic Chem., 1: 34-41 (1964); Kandasamy Ramasamy, et al., J. Chem, So., Chem. Commun., 560-562 (1989); and John A. Secrist, et al., J, Org. Chem., 43: 3937-3941 (1978).
The present invention provides regiospecific processes for preparing 5-substituted pyrrolo[2,3-d]primidines which are useful as intermediates for the preparation of, inter alia, pharmaceutically active pyrrolo[2,3-d]pyrimidine compounds, or as pharmaceutically active compounds.
The present invention further provides a regiospecific process for preparing 5-substituted pyrrolo[2,3-d]pyrimidine compounds, wherein said process is carried out in the same vessel.